A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis

Chao Quan, Qian Du, Min Li, Ruizhen Wang, Qian Ouyang, Shu Su, Sangsang Zhu, Qiaoli Chen, Yang Sheng, Liang Chen, David G. Campbell, Carol MacKintosh, Zhongzhou Yang, Kunfu Ouyang, Hong Yu Wang (Lead / Corresponding author), Shuai Chen (Lead / Corresponding author)

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Abstract

Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/β or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.

Original languageEnglish
Article number2186
Number of pages14
JournalNature Communications
Volume11
DOIs
Publication statusPublished - 4 May 2020

Keywords

  • Calcium signalling
  • Cardiomyopathies
  • Insulin signalling
  • Kinases

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